Metastatic liver disease is an important manifestation of many malignancies, particularly of the gastrointestinal tract (colon, pancreas) and with other tumors such as malignant melanoma. Colon cancer is the second leading cause of death in non-smoking males (Rice, RP, 1990), and accurate staging is essential for optimal humane management of victims of this disease. Similarly, accurate staging of pancreatic adenocarcinoma is important to minimize unncessary surgery for patients with spread of tumor to the liver. Diseases of the biliary track are also extremely common, with stones and inflammation as well as tumors involving the bile ducts and gallbladder. Thus, diagnostic visualization of the liver and bile ducts is one of the most common and important tasks of the diagnostic radiologist working in the field of abdominal radiology.
During the last decade, computed tomography (CT) has been the method of choice to detect and characterize focal disease of the liver, despite its limitations (Freeny, PC, et al 1983, 1986; see "Literature Cited", supra). Although several studies have demonstrated that the intravenous bolus administration of iodinated contrast agents does improve the sensitivity of CT to detect individual liver lesions, the overall efficacy and practicality of this approach has been felt to be less than ideal for the workup of patients with suspected focal liver lesions (Heiken, JP, et al, 1989). Because of the physical requirement of x-ray imaging, gram quantities of iodinated material are required for useful contrast enhancement. Hepatorophic, lipid soluble, radiographic contrast molecules have been more toxic than the more widely used water soluble agents, and have been better tolerated as oral dose forms (Lasser, EC, 1967). It is well known that these agents do not sufficiently concentrate in the liver to provide CT contrast enhancement.
Ultrasound is commonly used as a screening technique to evaluate for biliary tract and gallbladder stones, but ductal obstruction usually has to be evaluated with radioisotopic nuclear medicine scans (using, e.g., .sup.99m Tc-HIDA, an immidoacetic acid complex), and use of invasive techniques such as endoscopic retrograde pancreatocholangiography (ERCP) or percutaneous transhepatic cholangiography. The only current technique for visualizing both the hepatic parenchyma and the biliary collecting structures simultaneously is the nuclear scan.
Recently, magnetic resonance imaging (MRI) of focal liver lesions has received considerable attention (Heiken JP, et al, 1989; Schmiedel U, et al, 1990; Stark, DD, et al., 1987, 1988). Several studies have shown that the sensitivity of a liver MRI study using multiple pulse sequences for detecting individual metastatic deposits was only 64%, which is somewhat higher than 51% reported in one study for contrast enhanced CT (Stark, DD, et al, 1987).
MRI techniques for visualizing liver parenchymal pathology are evolving rapidly, with increasing scan speeds allowing single breath hold or even more rapid images to be obtained of the liver with contrast characteristics making the procedures competitive with contrast enhanced CAT scanning (Mirowitz SA, 1990). However, sensitivity of both imaging modalities with the use of intravenous contrast material remains limited (Heiken JP et al., 1989).
With the advent of modern MRI imaging, allowing contrast discrimination of about 500 times that of x-ray, new possibilities for contrast media development arise. For example, effective contrast enhancement may be achieved with chemicals that would be too toxic in the dose range needed for radiography (Runge, VM, et al., 1983). MRI provides methods to obtain sophisticated chemical information from the living body non-invasively. Important additional contrast information can be obtained by varying the NMR pulse sequence. Causing tissue specific contrast enhancement with a fixed imaging sequence is important for refining the contrast sensitivity of such a sequence, and may speed up the imaging procedure and aid in MRI image guided intervention. Although "ideal characteristics" of an NMR contrast agent have been discussed (Brasch RC, 1982), these can vary with the task at hand. For interventional work, persistence of contrast enhancement is an advantage. For evaluation of renal function, fast renal excretion would be preferred. Current diagnostic evaluation of the liver and urinary system depends upon a mixture of techniques and procedures utilizing ultrasound, x-ray, computerized tomography, and nuclear medicine. Positive prolonged contrast enhancement of the liver and extrahepatic binary collecting structures, heretofore unavailable in the art, would be an ideal use of a contrast agent in the clinical setting.
Various contrast agents for liver MRI enhancement have been investigated, but known procedures and agents remain less than optimal. For example, the usefulness of gadopentetate dimeglumine (also known as "Gd-DTPA", and commercially available under the name Magnevist, from Berlix, N.J.), a water soluble, extracellular fluid MRI contrast agent for the assessment of focal liver lesions remains equivocal (Mirowitz et al., 1990, Schmiedl U. et al 1990). Gd-DTPA, by a mechanism similar to conventional iodinated contrast agents, rapidly equilibrates with the interstitial fluid space in both normal liver and pathological tissue following intravenous administration and nonselectively enhances either normal liver, focal liver lesions or both, depending on the timing of the image acquisition with the contrast media administration. In addition, Gd-BOPTA, a lipophilic gadolinium chelate which undergoes hepatic excretion and opacifies the bile ducts has recently been described and studied (Patrizio G et al, 1990), but there has been little work to ascertain its stability.
An alternative approach to contrast enhancement of the liver is the use of particulate agents for MRI, largely because particulate agents are selectively taken up into normal reticuloendothelial (RE) tissues. These materials, consisting of iron-oxide particles of various sizes are currently being evaluated as intravenous contrast agents to improve the sensitivity of MRI towards detection of focal liver lesions (Stark, DD, et al, 1988; Majumdar, S., et al, 1990). Ferromagnetic particles are typically used as "negative" contrast agents, i.e. they highlight a lesion by decreasing the signal of normal liver parenchyma. The widespread use of iron oxide particles has been limited to date by concerns about acute and chronic toxicity. Furthermore, this approach does not permit evaluation of the biliary system, which is closely related to hepatocyte function and frequently also of concern in the workup of patients with liver disease. Another particle candidate is the paramagnetic liposome, as discussed by Unger, et al (1989).
Porphyrins and other naturally occurring, and synthetic metallochemicals (Morton KA, et al., 1988) are interesting candidates for evaluation as paramagnetic contrast media. Porphyrins have long been known to cause localized photosensitization of tumors and may cause radiosensitization of certain tumors (Spikes, JD, 1975; Thomson, JM et al, 1971). Since the compounds are also strong metal chelators, they provide the possibility of combining the localizing characteristics of the porphyrin with the paramagnetic or radiation absorption properties of chelated metals. Several groups have recently published studies on the use of selected manganese porphyrins as MRI contrast agents, most of this work being with water soluble substances for evaluation of tumor contrast enhancement. (Fiel, RJ, et al, 1987, 1990; Patronas, NJ, et al, 1987; Chen, C-W, et al, 1984; Ogan, MD, 1987). Lipid soluble manganese porphyrins such as protoporphyrin and mesoporphyrin have also been studied (Jackson, LS, et al, 1985; Nelson et al 1986, 1990), Much of the reported work relating to porphyrin contrast media is directed toward the water soluble synthetic prophyrin, manganese tetrakis-(4-sulfonatophenyl)porphyrin or MnTPPS.sub.4 (Patronas, NJ, et al, 1987). Recently, Bohdiewicz, et al (1990), reported usign Mn-hematoporphyrin as a hepatobiliary agent, but from the extent of urinary excretion reported, the agent of Bohdiewicz, et al must have contained significant quantities of water soluble contaminants or have been at least partially converted to a water soluble metabolite.
Early work with protoporphyrin was complicated by poor solubility and apparent high toxicity, although tissue specific T1(inversion time) effects were clearly demonstrated in the liver (Jackson, LS, et al, 1985). Subsequent work, including limited imaging experiments, revealed that manganese protoporphyrin caused hepatic and biliary contrast enhancement while the more hydrophilic manganese uroporphyrin produced dramatic contrast effects in the kidneys and urine. Mn mesoporphyrin has also been evaluated for MRI contrast enhancement of brain gliomas (Nelson, 1987) and has been shown to provide contrast enhancement of normal hepatic tissue leading to improved diagnostic visualization of tumors and abscesses on T1 weighted MRI images at non-toxic doses (Nelson, JA, et al, Soc. Body Computed Tomography, 1990).
Although significant advances in MRI imaging have been made, significant problems in tissue specificity, bioavailability and toxicity remain. Successful identification of an enterally deliverable hepatobiliary specific MRI contrast agent would be of great significance in advancing the commonly encountered problem of localization and accurate staging of primary or metastatic hepatic malignancy, and in the diagnosis and management of the even more common problem of stones and inflammation in the bile ducts. A noninvasive, quantitative procedure for spatially accurate evaluation of liver function would also be a powerful new tool in the field of liver transplantation.